The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in IRF5 are associated with a wide-range of immune-mediated diseases, included IBD. We recently found that IRF5 is a critical determinant of the inter-individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, the mechanism through which it contributes to PRR-initiated signaling pathways in human cells is not well defined (SA 1). We hypothesize that IRF5 regulates PRR- initiated signaling and outcomes in human myeloid cells through a combination of mechanisms associated with its localization in both the cytoplasm and nucleus, ultimately contributing to its broad and critical role in regulating PRRs. The role of IRF in mediating differentiation of related cellular subsets (e.g. M1 vs. M2) will be explored (SA 2a). Moreover, how IRF5 affects clearance of both resident and pathogenic intestinal microbes is not known (SA 2b). Importantly, the mechanism through which IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA 3). We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis. We hypothesize that IRF5 will contribute to functions in multiple immune cell subsets essential in intestinal immune homeostasis in vivo, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens.